Ether and amide compounds and preparation of thereof as antidiadetics.

ABSTRACT

Ether and amide derivatives are disclosed, which are represented by the following formula (I) and its pharmaceutical acceptable salt, and which are useful for the treatment of diabetes.  
                 
 
     (with the provisos that (i) when A is —O—, then n is 2 or 3 (ii) when A is  
                 
 
     then n is 1 or 2. R 3  is OH—, CH 3 SO 2 NH—, CF 3 SO 2 NH—, CH 3 SO 2 NHCH 2 —, CF 3 SO 2 NHCH 2 —, HOOC—, CH 3 OOC—,  
                 
 
     HOOC—CH 2 SO 2 NH—, CF 3 —CH 2 SO 2 NH—,  
                 
 
     R 8 —NHSO 2 —, R 8 —NHSO 2 —CH 2 —, HOOC—CH 2 —O—, HSO 3 N═CH—, or R 9 —SO 2 NHCO—;  
     R 4  is H, OH, O-alkyl or O—CH 2 OCH 3 ;  
     R 5  is H, halogen atom, —CH 2 COOH or OH;  
     R 6  and R 7  are hydrogen, t-butyl or pyrolidyl;  
     R 8  is hydrogen or lower alkyl;  
     R 9  is alkyl or thienyl;  
     R 10  is lower alkyl)  
     or a pharmaceutically acceptable salt.

BACKGROUND OF THE INVENTION

[0001] Field of the Invention

[0002] This invention is regarding to new ether and/or amide derivativeswhich are useful for the treatment of diabetes and a pharmaceuticalcomposition containing these compounds as active ingredients.

[0003] Current Technology

[0004] Biguanide and sulfonyl urea derivatives have been used asanti-diabetics so far. But these compounds have some drawbacks. Forinstance, biguanide compounds cause diabetic acidosis and sulfonyl ureacompounds often cause hypoglycemia and it is required to be careful fortaking these drugs.

[0005] Recently, thiazolidine-2,4-dion derivatives are reported to haveblood glucose lowering activities.

[0006] For example, Troglitazone (T. Yoshioka et al., J.Med.Chem.1989,32,421), Pioglitazone (H. Ikeda et al., J.Med.Chem. 1992,35,2617)or Rosiglitazone (B. C. C. Cantello et al., J.Med.Chem. 1994,37, 3977)are mentioned as Thiazolidine-2,4-dione derivatives and Troglitazone isapplied for clinical use.

[0007] However, these thiazolidime-2,4-dione compound are reported tocause of liver toxicity (R. Perfetti et al., Diabetes/Metabolism Review1998,14(3),207) and further, side effect to troglitazone treatment havebeen reported. They include cardiomegaly and hepatic malfunction such asincreasements of amino transferase (AST), alanin transferees (ALT), andlactic dehydrogenase (LDH). (R. R. Henry, Endocrinol.Metab,Clin,NorthAm. 1997,26,553).

[0008] To alleviate the side effect of thiazolidine-2,4-dionederivatives, several non-thiazolidine-2,4-diones are reported such asoxazoline-2,4-diones are reported such as oxazoline-2,4-dione (R. L. Dowet al., J.Med.Chem. 1991,34,1538), 1-oxo-2,4-diazoline-3,5-dione (S. W.Goldstein et al., J.Med.Chem. 1993,36,2238), α-amino carboxylic acid (R.A. DeFronzo, Diabetes, 1988,37,667), and Dicarboxylic acid ester (H.Shinkai et al., J.Med.Chem.1998,41,1927).

[0009] The Subject of Invention

[0010] The present invention concerns ether and amide compounds whichenhance insulin action and show hypoglycemic activity with lowtoxicities and a pharmaceutical composition containing these compoundsas active ingredients.

[0011] A Solution to the Problem

[0012] After elaborated to make an anti-diabetic drug, the inventorsfound that new compounds as show general formula (I) had shown potentanti-diabetic activities and fulfilled this invention.

[0013] Namely, the invention is the compounds as shown in generalformula (I) and its pharmaceutically acceptable salts and a compositioncontaining these compounds as active ingredients.

R₁—A—R₂  (I)

[0014]

[0015] (with the provisos that (i) when A is —O—, then n is 2 or 3 (ii)when A is

[0016] then n is 1 or 2. R₃ is OH—, CH₃SO₂NH—, CF₃SO₂NH—, CH₃SO₂NHCH₂—,CF₃SO₂NHCH₂—, HOOC—, CH₃OOC—,

[0017] HOOC—CH₂SO₂NH—, CF₃—CH₂SO₂NH—,

[0018] R₈—NHSO₂—, R₈—NHSO₂—CH₂—, HOOC—CH₂—O—, HSO₃N═CH—, or R₉—SO₂NHCO—;

[0019] R₄ is H, OH, O-alkyl or O—CH₂OCH₃;

[0020] R₅ is H, halogen atom, —CH₂COOH or OH;

[0021] R₆ and R₇ are hydrogen, t-butyl or pyrolidyl;

[0022] R₈ is hydrogen or lower alkyl;

[0023] R₉ is alkyl or thienyl;

[0024] R₁₀ is lower alkyl).

[0025] Enforcement of Invention

[0026] 70 compounds are exemplified as follow, but the invention is notlimited to these compounds. Further the preparation of the compounds1-70 are exemplified in each experimental sections.

[0027] Typical preparations of the compounds of general formula (I)according to the invention are shown.

[0028] (I) The preparation of a compound of general formula (I) in which

[0029] A is —O—; R₂ is

[0030] (wherein: R₅, R₆, and R₇ have the above-mentioned meanings; n=2)

[0031] (a) In case of

[0032] R₁ is

[0033] in which R₃ is CH₃SO₂NH— or CF₃SO₂NH— and R₄ is H.

[0034] The compounds can be obtained by means of the following reactiondiagram: Asparatic acid β-methyl ester (2). (J.Arg.Chem.Soc.Japan,1951-1952,25,129):C.A.47,6065i or R. L. Prestige et al., J.Org.Chem.1975,40,3287 as a starting material is converted to compound (3) by theknown method (B. Helvin et al., J.Med.Chem. 1992,35,1853) and compound(3) is tosylated or mesylated to obtain compound (4). The couplingreaction of compound (4) with nitrophenol to obtain compound (5) andthen compound (5) is reduced with H₂—Pd/C to obtain compound (6) andcompound (6) is subjected to react with several sulfonyl chloride (7)and sulfonic acid anhydride (8) to obtain the compound of genaralformula (I).

[0035] (b) In case of

[0036] R₁ is

[0037] in which R₃ is HOOCCH₂SO₂NH— and R₄ is H.

[0038] The compounds can be obtained by mean of the following reactiondiagram:

[0039] The reaction of compound (6) and EtOOC.CH₂SO₂Cl as a sulfonylchloride, namely CH₃OOCCH₂SO₂Cl (9), to obtain the ester (11) and thencompound (11) is hydrolyzed to obtain the compound of genaral formula(I).

[0040] The above mentioned compound (9) is obtained by the chlorinationof sulfoacetic acid (HOOCCH₂SO₃H(10)) with SOCl₂ and then reacted withalcohol (R. L. Hinman et al. (J.Am.Chem. Soc. 1959,81,5655), (H. T. Leeet al., Bioorg.Med.Chem.Lett. 1998,8,289).

[0041] (c) In case of

[0042] R₁ is

[0043] in which R₃ is HOOC—CONH— and R₄ is H.

[0044] The compound can be obtained by means of the following reactiondiagram:

[0045] The reaction of compound (6) and methyloxalate to obtain compound(12) and compound (12) is hydrolyzed to obtain the compound of generalformula (I). Further compound (12) is N-alkylated with alkylhalide andther subjected to hydrolyze to obtain the compound of general formula(I).

[0046] in which R₃ is CH₃SO₂NHCH₂—, CF₃SO₂ NHCH₂— and HOOC—CONH—, and R₄is H.

[0047] The compound can be obtained by means of the following reactiondiagram:

[0048] Compound (4) is reacted with p-hydroxy benzaldehyde to obtaincompound (13) and compound (13) is subjected to reductive aminationusing benzylamine and sodium borohydride to obtain compound (14).

[0049] After debenzylation of compound (14) in H₂—Pd/C, compound (15) isobtained. Compound (15) is reacted with sulfonyl chloride, sulfonic acidanhydride, EtOOC.CH₂SO₂Cl or methyloxalate as the same manner as in caseof compound (6) and compound (12), then the compound of general formula(I) is obtained.

[0050] (e) In case of

[0051] R₁ is

[0052] in which R₃ is HOOC— or CH₃OOC— and R₄ is —OH or —O-alkyl.

[0053] As shown in the following reaction diagram,

[0054] compound (32) and compound (3) is subjected to the MITSUNOBUreaction to obtain the compound (33) which is the compound of generalformula (I).

[0055] Further, compound (33) can be converted to compound (34) andcompound (36) as shown in the following diagram.

[0056] (f) In case of

[0057] R₁ is

[0058] in which R₃ is NH₂SO₃— or alkyl-NHSO₂— and R₄ is —OH.

[0059] As shown in the following reaction diagram,

[0060] according to the literature method (J.Med.Chem. 1997,20,1235),compound (51) and (52) are obtained from resorcin dimethyl ether (50).

[0061] Further, obtained compounds (51) and (52) are reacted withcompound (4) to obtain general formula (I) as follow.

[0062] (g) In case of

[0063] R₁ is

[0064] in which R₃ is CH₃SO₂NH— or CF₃SO₂NH—.

[0065] As shown in the following reaction diagram,

[0066] compound (53) is subjected to the MITSUNOBU reaction to obtaincompound (54) and reduction of compound (54) yields compound (55).Compound (55) is converted to compound (56) according to the method ofthe preparation of compound (42) from compound (39).

[0067] (h) In case of

[0068] R₁ is

[0069] in which R₃ is —COOH.

[0070] As shown in the following reaction diagram,

[0071] compound (57) is reacted with compound (4) and obtain the ethercompound (58) and the resulting compound (58) is hydrolyzed to obtaincompound (59) which is the compound of general formula (I).

[0072] (i) In case of

[0073] R₁ is

[0074] in which R₃ is MeOOCCH₂—, and R₄ is —O-alkyl.

[0075] As shown in the following reaction diagram,

[0076] compound (61), which is obtained from compound (60), is reactedwith compound (4) to obtain the compound of general formula (I).

[0077] (j) In case of

[0078] R₁ is

[0079] in which R₃ is NH₂SO₂CH₂— or alkyl-NHSO₂CH₂— and R₄ is OH or—O-alkyl.

[0080] As shown in the following reaction diagram,

[0081] after reduction of compound (62), the obtained compound (63) isreacted with Na₂SO₃ to obtain compound (64) according to the reportedmethod (J.C.S.Chem.Comom., 1989,521). Then compound (64) is chlorinatedwith POCl₃ and treated with aqueous NH₃ to obtain the amide compound(65). After debenzylation of compound (65), compound (66) is obtained.Compound (66) is reacted with compound (4) to yield the compound ofgeneral formula (I).

[0082] (II) The preparation of a compound of general formula (I) inwhich

[0083] A is —O—; R₂ is

[0084] (wherein: R₅, R₆, and R₇ have the above mentioned meaning; n=3)

[0085] (a) In case of

[0086] R₁ is

[0087] in which R₃ is CH₃SO₂NH— or CF₃SO₂NH—, and R₄ is H.

[0088] As shown in the following reaction diagram,

[0089] glutamic acid γ-methyl ester (16) is used in stead of asparticacid β-methyl ester (2). Compound (17) is obtained from compound (16) bythe same method as compound (3) is obtained from compound (2).

[0090] After compound (17) is halogenated, tosylated or mesylated,obtained compound (18) is coupled with nitrophenol and the resultingcompound (19) is hydrogenated to obtain compound (20). The obtainedcompound (20) is reacted with several sulfonyl chlorides, sulfonic acidanhydrides, EtOOC.H₂SO₂Cl or methyloxalate to obtain the compound ofgeneral formula (I).

[0091] (III) The preparation of a compound of general formula (I) inwhich

[0092] A is —O—; R₂is

[0093] (a) In case of

[0094] R₁ is

[0095] in which R₃ is CH₃SO₂NH— or CF₃SO₂NH—, and R₄ is H.

[0096] As shown in the following reaction diagram,

[0097] after the reaction of 2-methyl 5-ethylpyridine (21) andformaldehyde using the reported method (Japanese Patent Publication,1981-65870), compound (22) is obtained. After compound (22) ishalogenated, tosylated or mesylated, obtained compound (23) is coupledwith nitrophenol and the resulting compound (24) is hydrogenated toobtain compound (25), by the same method as compound (4) is obtainedfrom compound (3).

[0098] The obtained compound (25) is reacted with severalsulfonylchlorides (7), sulfonic acid anhydrides (8), EtOOC.CH₂SO₂Cl ormethyloxalate to obtain the compound of general formula (I).

[0099] (b) In case of

[0100] R₁ is

[0101] in which R₃ is CH₃SO₂NH— or CF₃SO₂NH—, and R₄ is —OH or —O-alkyl.

[0102] As shown in the following reaction diagram,

[0103] compound (37) is reacted with HO—R₂ to obtain compound (38) andcompound (38) is hydrogenated to compound (39), or compound (38) isalkylated to compound (40) and reduction of compound (40) is resultingcompound (41) . Then compound (39) or (41) are reacted with RSO₂Cl andobtain compound (42) or compound (43).

[0104] Compound (37) in the diagram can be obtained from resorcin asfollow.

[0105] And compound (42) and (43) can be obtained by using the reportedmethod of coupling reaction of fluorobenzene and alcholol(Bioorg.Med.Chem.Lett., 1994,4 (10),1181). Namely, 2—OMOM (methoxymethyl)-4-fluoro nitrozenzene (45) is reacted with HO—R₂ to givecompound (46) and resulting compound (46) is reduced to obtain compound(47).

[0106] Compound (47) is reacted with RSO₂Cl to obtain compound (48) andafter deprotection of MOM-group in compound (48), compound (42) isobtained.

[0107] Instead of compound (45), compound (49) is also converted tocompound (41), and compound (43) is obtained from compound (41) by thesame method as compound (48) is obtained from compound (46).

[0108] The process is shown in the following reaction diagram.

[0109] (IV) The preparation of a compound of general formula (I) inwhich

[0110] A is —O—; R₂ is

[0111] (a) In case of

[0112] R₁ is

[0113] in which R₃ is CH₃SO₂NH— or CF₃SO₂NH—, and R₄ is —H.

[0114] As shown in the following reaction diagram,

[0115] compound (28), obtained from 2-chloropyridine (26) or 2-methylamino pyridine (27), is tosylated or mesylated to obtain compound (29).Compound (29) is subjected to coupling reaction with nitro phenol andobtained compound (30) using the same manner to obtain compound (3).Resulting compound (30) is reduced to obtain compound (31) and compound(31) is reacted several sulfonyl chlorides (7), sulfonic acid anhydrides(8), EtOOC.CH₂SO₂Cl and methyloxalate to obtain the compound of generalformula (I).

[0116] (V) The preparation of a compound of general formula (I) in which

[0117] A is —NH—CO—

[0118] (a) In case of

[0119] R₁ is

[0120] in which R₃ is CH₃SO₂NH— or CF₃SO₂NH—, and R₄ is —H.

[0121] As shown in the following reaction diagram,

[0122] compound (67), intermediate for compound (3), is obtainedaccording to the reported method (J.Med.Chem. 1999,35,1853) and compound(67) is hydrolyzed to obtain compound (68). After chlorination ofcompound (68), obtained chloride is reacted with p-nitroaniline toobtain compound (69).

[0123] Then compound (69) is hydrogenated to obtain compound (70)according to the same method to prepare compound (5). Compound (70) isreacted several sulfonyl chlorides (7), sulfonic acid anhydrides (8),EtOOC.CH₂SO₂Cl or methyloxalate to obtain the compound of generalformula (I).

[0124] (b) In case of

[0125] R₁ is

[0126] in which R₃ is R₉SO₂NHCO— (R₉=alkyl or thienyl), and R₄ is H.

[0127] As shown in the following reaction diagram,

[0128] carboxylic acid of compound (71) is reacted with CDI (CarbonylDiimidazole) and then subjected to react with sulfamine of compound (72)in the presence of DBU (1,8-Diazabicyclo[5,4,0]undeca-7-ene) and obtainthe compound of general formula (I). (Bioorg.Med.Chem. Lett. 1995,1155)

[0129] As pharmaceutical acceptable salts of a compound of generalformula (I), sodium salt, potassium salt and inorganic base arementioned.

[0130] In case of R₁ contains pyridine base, salts of inorganic andorganic acids are mentioned. As the salt of inorganic acid,hydrochloride and sulfate are mentioned. As the salt of organic acid,acetate, succinate and fumalate are mentioned.

[0131] A compound of general formula (I) can be used itself orformulated to pharmaceutical product such as powder, granule, tablet andcapsule by known pharmaceutical technology.

Pharmacological Experiment

[0132] Hypoglycemic activity in mice

[0133] Test compounds were suspended in 0.5% Methyl cellulose solutionand administered (p.o.) to db/db mice (obtained from Nihon Clea) at arange of 3-30 mg/kg once a day for four consecutive days. Troglitazone(300 mg/kg) was also administered for control. The results is shown inTable 1.

[0134] The compound number corresponds to the experimental number. TABLE1 Compound No. Dosage (mg/kg) Hypoglycemic activity (%) 1 30 24.6 2 1049.0 8 10 26.0 9 10 24.0 10 10 32.4 11 10 15.4 18 10 34.7 19 10 12.8 2110 34.6 24 10 25.7 26 30 15.1 30 30 22.1 31 30 19.0 35 30 28.8 40 3053.4 42 10 29.6 47 10 25.6 48 30 65.4 50 30 21.9 52 30 10.5 57 3 44.0 583 43.4 59 3 18.4 63 3 18.4 67 3 33.1 68 3 21.2 70 30 51.0 Troglitazone300 34.0

EXAMPLE

[0135] The following Examples are provided only for the purpose of thepreparation of the compound and not restrict the disclosed invention.

Example 1

[0136] 4-[2-(5-Methyl-2-phenyl-1,3-oxazole-4-yl)ethoxy]benzenemethylsulfonamide

[0137] (a) 5-Methyl-4-tosyloxyethyl-2-phenyl-oxazole

[0138] 22.2 g of 5-Methyl-4-hydroxyethyl-2-phenyl-oxazole was dissolvedin a mixture of pyridine (13 mL) and dichloroethane (6 mL) andtoluenesulfonyl chloride was added slowly to the mixture and stirred atroom temperature over night. The reaction mixture was poured into waterand extracted with ethyl acetate (50 mL) . The organic extract waswashed with satd. CuSO₄ solution, H₂O and satd. NaCl solution. Removalof solvents after drying over anhydro. Na₂SO₄, followed by columnchromatography (ethyl acetate:n-hexane=1:1) yielded 3.33 g (87.6%) of awhite solid of the objective compound.

[0139] MASS(m/e):371(M+),216,186(BP),156,130,105,77,51

[0140] IR(cm⁻¹):1359,1173,966,927,834,813,753,666

[0141]¹HNMR(CDCl₃) δ: 2.01-2.08 (m, 2H, —CH₂—), 2.29 (S, 3H, —CH₃), 2.42(S, 3H, —CH₃), 2.55 (t, 2H, —CH₂—, J=6.83,7.33 Hz), 4.08 (t, 2H, —CH₂—,J=5.86,6.34 Hz), 7.31 (d, 2H, aromatic, J=7.81 Hz), 7.40-7.43 (m, 3H,aromatic), 7.78 (d, 2H, aromatic, J=8.3 Hz), 7.93 (dd, 2H, aromatic,J=7.33, 7.81 Hz)

[0142] (b) 5-Methyl-4-p-nitrophenoxyethyl-2-phenyl-1,3-oxazole

[0143] 0.21 g of NaH was placed in a 50 mL flask and washed twice withn-hexane and added 10 mL of dimethylformamide. 0.67 g of p-nitrophenolwas added to the solution at 0° C. and stirred for 30 min. To thismixture, the compound (1.8 g) obtained from the above mentioned step (a)in dimethyl formamide (5 mL) was added and stirred at 80° C. over night.After cooling, the reaction mixture was poured into water and theproduct was extracted with ethyl acetate (80 mL). The ethyl acetatephase was washed with H₂O, satd. NaCl solution and dried over Na₂SO₄ andfiltered. Evaporation of the filtrate gave a residue, from which 1.24 g(75.6%) of the yellowish objective compound was obtained by silicagelcolumn chromatography (ethyl acetate:n-hexane=1:3). m.p.=100-103° C.

[0144] MASS(m/e):338(M+),200,173(BP),130,104,77,51

[0145] IR(cm⁻¹):1590,1500,1332,1263,1107,840

[0146]¹HNMR(CDCl₃) δ: 2.18-2.24 (m, 2H, —CH₂—), 2.29 (S, 3H, —CH₃), 2.71(t, 2H, —CH₂—, J=7.33, 6.83 Hz), 4.09 (t, 2H, —CH₂—, J=6.35, 5.86 Hz),6.95 (d, 2H, aromatic, J=9.28 Hz), 7.41-7.44 (m, 3H, aromatic), 7.97(dd, 2H, aromatic, J=7.32, 7.82 Hz), 8.19 (d, 2H, aromatic, J=9.28 Hz)

[0147] (c) 5-Methyl-4-p-aminophenoxyethyl-2-phenyl-1,3-oxazole

[0148] 1.23 g of the compound obtained from the above mentioned step (b)was dissolved in a solution of 25 mL of methanol-tetrahydrofuran (1:1)and added 0.25 g of 5% Pd—C. To this solution was introducedhydrogen-gas for 1 hour. After filtration of the reaction mixture, thefiltrate was evaporated to give a residue, from which 1.02 g (91.1%) ofthe objective compound was obtained by silicagel column chromatography(ethyl acetate:n-hexane=1:1). m.p.=57-59° C.

[0149] MASS(m/e):308(M+),200(BP),174,104,80,53

[0150] IR(cm⁻¹):1512,1242,825,711,681

[0151]¹HNMR(CDCl₃) δ: 2.08-2.15 (m, 2H, —CH₂—), 2.28 (S, 3H, —CH₃), 2.68(t, 2H, —CH₂—, J=7.33, 7.32 Hz), 3.42 (bs, 2H, —NH₂), 3.90 (t, 2H,—CH₂—, J=6.35, 5.86 Hz), 6.62-6.66 (m, 2H, aromatic), 6.73-6.76 (m, 2H,aromatic), 7.38-7.45 (m, 2H, aromatic), 7.96-7.99 (m, 2H, aromatic)

[0152] (d) 4-[2-(5-Methyl-2-phenyl-1,3-oxazole4-yl)ethoxy]benzenemethylsulfonamide (compound 1)

[0153] To a mixture of 0.4 g of the compound obtained from the abovementioned step (c) and 0.28 mL of triethylamine in dichloroethane (4 mL)and 0.16 mL of mesyl chloride were added and stirred at 30° C. for 30minutes. The reaction mixture was poured into water and extracted withethyl acetate. The ethyl acetate phase was washed with satd. NH₄Clsolution, water and satd. NaCl solution and dried over anhydrous Na₂SO₄and filtrated. Evaporation of the filtrate gave a residue, from which0.34 g (66.7%) of the off-white objective compound was obtained bysilicagel column chromatography (ethyl acetate:n-hexane =1:1).m.p.=121-123° C.

[0154] MASS(m/e):372(M+),264,186(BP),149,104,79,55

[0155] IR(cm⁻¹):3238,1506,1320,1281,1245,1212,1143,777

[0156]¹HNMR(CDCl₃) δ: 2.38 (S, 3H, —CH₃), 2.93 (S, 3H, —SO₂CH₃), 2.98(t, 2H, —CH₂—, J=6.35, 6.84 Hz), 4.23 (t, 2H, —CH₂—, J=6.83, 6.84 Hz),6.25 (S, 1H, —NH), 6.88 (d, 2H, aromatic, J=8.79 Hz), 7.16 (d, 2H,aromatic, J=9.27 Hz), 7.39-7.45 (m, 3H, aromatic), 7.97 (dd, 2H,aromatic, J=1.46, 1.95 Hz)

Example 2

[0157] 4-[2-(5-Methyl-2-phenyl-1,3-oxazole4-yl)ethoxy]benzenetrifluoromethyl sulfonamide (compound 2)

[0158] To a mixture of the compound (0.4 g) obtained from Example 1 step(c) in 4 mL of dichloromethane and 0.27 mL of triethylamine was addedtrifluoromethanesulfonic acid anhydride (3.3 mL) and stirred for 30minutes at 0° C. To the reaction mixture were added 2 mL of methanol and1 mL of 10% NaOH solution and the mixture was stirred for 10 minutes,followed by addition of water (20 mL) and extracted with ethyl acetate.The extract was washed with satd. NH₄Cl, water and satd. NaCl and driedover anhydrous Na₂SO₄. After filtrating, the extract was evaporated andthe residue was purified by silicagel column chromatography. Using aeluants (ethyl acetate:n-hexane=1:1), 0.38 g (66.7%) of the objectivecompound was obtained. m.p.=97-99° C.

[0159] MASS(m/e):441 (M+),200(BP),173,104,69

[0160] IR(cm⁻¹): 1455,1248,1215,1116,894,597

[0161]¹HNMR(CDCl₃) δ: 2.17-2.23 (m, 2H, —CH₂—), 2.29 (S, 3H, —CH₃), 2.70(t, 2H, —CH₂—, J=6.83, 7.33 Hz), 4.05 (t, 2H, —CH₂—, J=5.86, 6.34 Hz),6.97 (d, 2H, aromatic, J=8.79 Hz), 7.40-7.44 (m, 3H, aromatic), 7.98(dd, 2H, aromatic, J=7.32, 8.30 Hz)

Example 3

[0162]5-Methyl-4-[2-(4-carboxymethylsulfonylamino)phenoxy]ethyl-2-phenyl-1,3-oxazole(compound 3)

[0163] (a) 5-Methyl-4-[2-(4-ethoxycarbonylmethylsulfonylamino)phenoxy]ethyl-2-phenyl-oxazole

[0164] To a solution of the compound (0.36 g) obtained from the abovementioned Example 1 step (c) and triethylamine (0.26 mL) indichloroethane (8 mL) was slowly added ethoxy carbonyl chloride (0.27 g)at 0° C. and stirred for 2 hours. The reaction mixture was poured intowater and the product was extracted with ethyl acetate. The extract waswashed with satd. NH₄Cl, water and satd. NaCl and dried over anhydrousNa₂SO₄ and filtrated. Evaporation of the filtrate gave a residue, fromwhich 0.32 g (59.1%) of the oily objective compound was obtained bysilicagel column chromatography (ethyl acetate:n-hexane =1:1).

[0165] MASS(m/e):443(M+),186(BP),144,108,84,47

[0166] IR(cm⁻¹): 1734,1341,1299,1248,1158,753

[0167]¹HNMR(CDCl₃) δ: 1.32 (t, 3H, —COOEt, J=6.84, 7.32 Hz), 2.38 (S,3H, —CH₃), 2.98 (t, 2H, —CH₂—, J=6.83, 6.35 Hz), 3.86 (S, 2H, —CH₂—),4.23 (t, 2H, —CH₂—, J=6.83, 6.35 Hz), 4.28 (q, 2H, —COOEt, J=7.32, 6.83Hz), 6.74 (S, 1H, —SO₂NH), 6.88 (d, 2H, aromatic, J=8.78 Hz), 7.25 (d,2H, aromatic, J=8.30 Hz), 7.39-7.44 (m, 3H, aromatic), 7.97 (q, 2H,aromatic, J=1.46, 1.96 Hz)

[0168] (b) 5-Methyl-4-[2-(4-carboxymethylsulfonylamino)phenoxy]ethyl-2-phenyl-1,3-oxazole (compound 3)

[0169] To a solution of the compound (0.3 g) obtained from the abovementioned step (a) in ethanol (5 mL) was added 10% NaOH (2.5 mL) and thesolution was stirred for 1 hour. After removing the solvent, the residuewas dissolved in water and washed with ether. After acidification with10% HCl, the water phase was extracted with ethyl acetate. The ethylacetate phase was washed with water, satd. NaCl and dried over anhydrousNa₂SO₄. After removing the solvent, the residue was recruptallized fromethyl acetate. 0.2 g (71.4%) of the objective compound was obtained.m.p.=164-167° C.

[0170] MASS(m/e):371(M+—COOH),294,186(BP),144,104,77

[0171] IR(cm⁻¹):3274,1713,1512,1338,1281,1245,1158,1107

[0172]¹HNMR (CDCl₃) δ:2.42 (S, 3H, —CH₃), 3.06 (t, 2H, —CH₂—, J=6.35Hz), 3.86 (S, 2H, —CH₂—), 4.24 (t, 2H, —CH₂—, J=6.83, 6.35 Hz), 6.85 (d,2H, aromatic, J=9.28 Hz), 7.22 (d, 2H, aromatic, J=8.78 Hz), 7.45-7.47(m, 3H, aromatic), 7.95 (q, 2H, aromatic, J=2.44, 3.9 Hz)

Example 4-5

[0173] According to the method described in Example 3, compound 4 (oil),compound 5 (m.p.=273-239° C.), compound 6 (m.p.=143-145° C.) andcompound 7 (m.p.=114-116° C.) were obtained.

Example 8

[0174]2-[4-(2-(5-Methyl-2-phenyl-1,3-oxazole4-yl)ethoxy)phenyl]amino-2-oxo-aceticacid (compound 8)

[0175] (a)2-[4-(2-(5-Methyl-2-phenyl-1,3-oxazole-4-yl)ethoxy)phenyl]amino-2-oxo-aceticacid methyl aster

[0176] A mixture of the compound (0.5 g) obtained from the abovementioned Example 1 step (c) and methyl oxalate (0.6 g) in methanol (10mL) was refluxed over night. After cooling, the solvent was evaporatedand a resulting residue was purified by silicagel column chromatography.Chloroform was used as a eluant. 0.55 g (84.6%) of the objectivecompound was obtained. m.p.=128-132

[0177] MASS(m/e):380(M+),321,186(BP),144,105,59

[0178]¹HNMR(CDCl₃) δ: 2.37 (S, 3H, —CH₃), 2.98 (t, 2H, —CH₂—, J=6.84,6.35 Hz), 3.96 (S, 3H, —COOMe), 4.24 (t, 2H, —CH₂—, J=6.35, 6.83 Hz),6.90 (d, 2H, aromatic, J=8.79 Hz), 7.38-7.44 (m, 3H, aromatic), 7.53 (d,2H, aromatic, J=8.79 Hz), 7.97 (d, 2H, aromatic, J=5.86 Hz), 8.76 (d, S,1H, —NH)

[0179] (b)2-[4-(2-(5-Methyl-2-phenyl-1,3-oxazole-4-yl)ethoxy)phenyl]amino-2-oxo-aceticacid (compound 8)

[0180] A mixture of the compound (0.53 g) obtained from the abovementioned Example 8 step (a) and 10% NaOH in methanol (15 mL) wasstirred for 1 hour and water (30 mL) was added to the mixture, followedby acidification (pH 4) with 10% HCl to give a crptalline product.Recrystallization from ethyl acetate gave the objective compound (0.42g, 82.3%). m.p.=196-198° C.

[0181] MASS(m/e):366(M+),322,294,186(BP),144,104,77

[0182]¹HNMR(CDCl₃) δ: 2.36 (S, 3H, —CH₃), 2.92 (t, 2H, —CH₂—, J=6.35,6.83 Hz), 3.32 (bs, 1H, —NH), 4.19 (t, 2H, —CH₂—, J=6.34, 6.84 Hz), 6.93(d, 2H, aromatic, J=9.27 Hz), 7.45-7.55 (m, 3H, aromatic), 7.67 (dd, 2H,aromatic, J=2.44 Hz), 7.91 (dd, 2H, aromatic, J=1.47, 1.95 Hz)

Example 9

[0183]2-[4-(2-(5-Methyl-2-phenyl-1,3-oxazole-4-yl)ethoxy)benzyl]trifluoromethylsulfonamide(compound 9)

[0184] (a)5-Methyl-4-(2-p-benzylaminophenoxy)-ethyl-2-phenyl-1,3-oxazole

[0185] A mixture of5-methyl-4-[2-(p-formylphenoxy)]ethyl-2-phenyl-1,3-oxazole (0.54 g) andbenzylamine (0.21 mL) in methanol (10 mL) was stirred for 10 minutes andNaBH₃CN (0.11 g) was added to the mixture. The mixture was stirred overnight and evaporated and to a resulting residue was added 10% HCl withstirring, followed by addition of satd. NaHCO₃ to alkalize. The productwas extracted with ethyl acetate. The ethyl acetate phase was washedwith H₂O, satd. NaCl and dried over anhydrous Na₂SO₄ and filtered.Evaporation of the filtrate gave a residue, from which 0.43 (61.4%) ofthe oily objective product was obtained by silicagel columnchromatography.

[0186] MASS(m/e):398(M+),291,212,186(BP),146,104,77

[0187] IR(cm⁻¹):3022,2914,1608,1509,1452,1242,738,714

[0188]¹HNMR(CDCl₃) δ: 2.37 (S, 3H, —CH₃), 2.98 (t, 2H, —CH₂—, J=6.83,6.84 Hz), 3.73 (S, 2H, —CH₂—), 3.78 (S, 2H, —CH₂—), 4.24 (t, 2H, —CH₂—,J=6.84, 6.83 Hz), 6.86 (d, 2H, aromatic, J=8.79 Hz), 7.21-7.44 (m, 10H,aromatic), 7.97 (q, 2H, aromatic, J=1.46, 1.95 Hz)

[0189] (b) 5-Methyl-4-(2-p-aminophenoxy)ethyl-2-phenyl-1,3-oxazole

[0190] The compound (0.4 g) obtained from the above mentioned Example 9step (a) was dissolved in methanol (10 mL) containing a small amount ofHOAc and 5% Pd—C (80 mg). The mixture is hydrogenated and the reactionmixture was filtered and the filtrate was evaporated. A resultingresidue was purified by silicagel column chromatography using a eluant(CHCl₃:MeOH=10:1). The objective compound (0.21 g, 67.7%) was obtained.m.p.=149-152° C.

[0191] MASS(m/e):308(M+),291,186(BP),144,122,104,77

[0192] IR(cm⁻¹):3430,2962,1608,1248

[0193]¹HNMR(CDCl₃) δ: 3.88 (S, 2H, —CH₂—), 4.23 (t, 2H, —CH₂—, J=6.34,6.84 Hz), 6.90 (d, 2H, aromatic, J=8.79 Hz), 7.27 (d, 2H, aromatic,J=8.78 Hz), 7.41-7.46 (m, 3H, aromatic), 7.96 (d, 2H, aromatic, J=7.81Hz)

[0194] (c)2-[4-(2-(5-Methyl-2-phenyl-1,3-oxazole4-yl)ethoxy)benzyl]trifluoromethylsulfonamide (compound 9)

[0195] The compound (0.14 g) obtained from the above mentioned Example 9step (b) was reacted with trifluoromethanesulfonamide as same manner asExample 2 and the objective compound (compound 9) was obtained (0.55 g,28%). m.p.=113-115° C.

[0196] MASS(m/e):440(M+),186,144,104(BP),77

[0197] IR(cm⁻¹):3310,1443,1368,1251,1227,1188,1146

[0198]¹HNMR(CDCl₃) δ: 2.38 (S, 3H, —CH₃), 2.98 (t, 2H, —CH₂—, J=6.83,6.84 Hz), 4.25 (t, 2H, —CH₂—, J=6.84, 6.34 Hz), 4.37 (d, 2H, —CH₂—,J=4.89 Hz), 5.05 (bs, 1H, —NHSO₂—), 6.90 (d, 2H, aromatic, J=8.79 Hz),7.22 (d, 2H, aromatic, J=8.79 Hz), 7.41-7.45 (m, 3H, aromatic), 7.97 (q,2H, aromatic, J=1.95, 1.96 Hz)

Example 10

[0199] 4-[2-(5-Ethylpyridine-2-yl)ethoxy]benzenetrifluoromethylsulfonamide (compound 10)

[0200] (a) 2-[2-(4-Nitrophenoxy)]ethyl-5-ethyl-pyridine

[0201] To a mixture of 2-(5-ethylpyridine) ethanol (10 g) and4-fluoronitrobenzene (9.3 g) in Dimethylformamide (100 mL) was addedNaOH (3.4 g) and the mixture was stirred at 0° C. for 1 hour. Afterpouring into ice-water, the product was extracted with ethyl acetate(150 mL). The ethyl acetate phase was washed with satd. NaCl and driedover anhydrous Na₂SO₄. After removing the solvent, the resulting residuewas purified by silicagel column chromatography(EtoAc:n-hexane=1:2→2:1). Recrystallization from EtoAc n-hexane mixture(1:1) gave the off-white objective compound. 13.4 g (74.4%), m.p.=45-47°C.

[0202] MASS(m/e):272(M+), 150,134(BP), 119,93,77

[0203] IR(cm⁻¹):1593,1518,1491,1341,1260,1008,834

[0204]¹HNMR(CDCl₃) δ: 1.25 (t, 3H, —C₂H₅, J=7.81, 7.32 Hz), 2.64 (q, 2H,—C₂H₅, J=7.33, 7.32 Hz), 3.27 (t, 2H, —CH₂—, J=6.34, 6.84 Hz), 4.46 (t,2H, —CH₂—, J=6.34, 6.84 Hz), 7.17 (d, 1H, pyridine, J=8.31 Hz), 7.47(dd, 1H, pyridine, J=2.44, 2.45 Hz), 8.18 (dd, 2H, aromatic, J=6.83,7.32 Hz), 8.40 (d, 1H, pyridine, J=1.95 Hz)

[0205] (b) 2-[2-(4-Aminophenoxy)]ethyl-5-ethyl-pyridine

[0206] The compound (1.85 g) obtained from the above mentioned Example10 step (a) was hydrogenated as same manner as Example 1 step (c) andobtained the oily objective compound (1.62 g, 98.2%).

[0207] MASS(m/e):242(M+), 134(BP), 119,106,83,65

[0208] IR(cm⁻¹):2950,1509,1233,822

[0209]¹HNMR(CDCl₃) δ: 1.24 (t, 3H, —C₂H₅, J=7.81, 7.33 Hz), 2.62 (q, 2H,—C₂H₅, J=7.33 Hz), 3.19 (t, 2H, —CH₂—, J=6.35, 6.83 Hz), 3.42 (bs, 2H,—NH₂), 4.26 (t, 2H, —CH₂—, J=6.35, 6.84 Hz), 6.61-6.64 (m, 2H,aromatic), 6.72-6.76 (m, 2H, aromatic), 7.18 (d, 1H, pyridine, J=7.81Hz), 7.44 (dd, 1H, pyridine, J=1.95, 1.96 Hz), 8.39 (d, 1H, pyridine,J=2.46 Hz)

[0210] (c) 4-[2-(5-Ethylpyridine-2-yl)ethoxy]benzenetrifluoromethylsulfonamide (compound 10)

[0211] The compound (1.2 g) obtained from the above mentioned Example 10step (b) was reacted with trifluoromethanesulfonic acid anhydride by thesame procedure described in Example 2 and obtained 0.3 g the objectivecompound (compound 10). m.p.=76-78° C.

[0212] MASS(m/e):373(M+−1),134(BP),91,69

[0213] IR(cm⁻¹):1446,1263,1119,897,603

[0214]¹HNMR(CDCl₃) δ: 1.25(t, 3H, —C₂H₅, J=7.81, 7.33 Hz), 2.63 (q, 2H,—C₂H₅, J=7.32, 7.82 Hz), 3.25 (t, 2H, —CH₂—, J=6.83, 6.35 Hz), 4.39 (t,2H, —CH₂—, J=6.35 Hz), 6.96 (dd, 2H, aromatic, J=6.84, 6.83 Hz), 7.18(d, 1H, pyridine, J=7.81 Hz), 7.28 (d, 2H, aromatic, J=9.28 Hz), 7.46(dd, 1H, pyridine, J=7.81 Hz), 8.40 (d, 1H, pyridine, J=1.96 Hz)

Example 11

[0215] 4-[2-(N-Methyl-N-2-pyridyl)aminoethoxy]benzenetrifluoromethanesulonamide (compound 11)

[0216] (a)4-[2-(N-Methyl-N-2-pyridyl)aminoethoxy]-1-nitrobenzene-2-pyridyl-2-methylaminoethanol (4.0 g) was reacted with 4-fluorobenzene by the same proceduredescribed in Example 6 step (a) and obtained the oily objective compound(5.9 g, 82.2%).

[0217] MASS(m/e):273(M+),139,121(BP),94,78,51

[0218] IR(cm⁻¹):2926,1590,1497,1425,1338,1260

[0219]¹HNMR(CDCl₃) δ: 3.14 (S, 3H, —CH₃), 4.03 (t, 2H, —CH₂, J=5.86,5.37 Hz), 4.30 (t, 2H, —CH₂—, J=5.86 Hz), 5.52 (d, 1H, pyridine, J=8.79Hz), 6.59 (t, 1H, pyridine, J=4.88, 6.35 Hz), 6.97 (dd, 2H, aromatic,J=8.79 Hz), 7.45-7.50 (m, 1H, pyridine), 8.15-8.20 (m, 2H, pyridine,aromatic)

[0220] (b) 4-[2-(N-Methyl-N-2-pyridyl)aminoethoxy]-1-aminobenzene

[0221] The compound (5.85 g) obtained from the above mentioned Example11 step (a) was hydrogenated by the same procedure described in Example1 step (c) and obtained the objective compound (2.12 g, 40.7%).

[0222] MASS(m/e):243(M+), 135(BP),121,108,94,78,65

[0223] IR(cm⁻¹):3334,2914,1596,1557,1503,1425,1233,771

[0224] (c) 4-[2-(N-Methyl-N-2-pyridyl)aminoethoxy]benzenetrifluoromethanesulfonamide (compound 11)

[0225] The compound (0.5 g) obtained from the above mentioned Example 11step (b) was reacted with trifluoromethanesulfonamide by the sameprocedure described in Example 2 and obtained the objective product(0.67 g, 87.0%). m.p.=60-62° C.

[0226] MASS(m/e):375(M+),304,170,135,108,78(BP),52

[0227] IR(cm⁻¹):1593,1503,1452,1218,1125,891,600

[0228]¹HNMR(CDCl₃) δ: 3.13 (S, 3H, —CH₃), 4.01 (t, 2H, —CH₂, J=5.86,5.37 Hz), 4.24 (t, 2H, —CH₂—, J=5.86, 5.37 Hz), 6.51 (d, 1H, pyridine,J=8.30 Hz), 6.57 (t, 1H, pyridine, J=4.88, 6.84 Hz), 6.97 (d, 2H,aromatic, J=9.27 Hz), 7.27 (d, 2H, aromatic, J=9.77 Hz), 7.44-7.49 (m,1H, pyridine), 8.15 (d, 1H, pyridine, J=3.90 Hz)

Example 12-17

[0229] According to the method described in Example 1, compound 12(m.p.=106-108° C.), compound 13(m.p.=67-68° C.), compound 14(m.p.=56-58° C.), compound 15 (m.p.=128-130° C.), compound 16 (126-127°C.) and compound 17 (m.p.=128-130° C.) were obtained.

Example 18-20

[0230] According to the method described in Example 2, compound 18(m.p.=197-198° C.), compound 19 (m.p.=70-71° C.) and compound 20(m.p.=170-172° C.) were obtained.

Example 21

[0231] 5-Methyl-4-(3-hydroxy)propyl-2-phenyl-1,3-oxazole, prepared fromglutamic acid instead of asparatic acid, was reacted as a similar mannerdescribed in Experimental 2 and obtained compound 21 (m.p.=113-114° C.).

Example 22-24

[0232] According to the same procedure described in Example 4, compound22 (m.p.=128-130° C.) and compound 23 (m.p.=217° C. (decomp.)) wereobtained.

Example 25

[0233] 2—Hydroxy-4-[2-(5-methyl-2-phenyl-1,3-oxazole4-yl)ethoxy]benzoicacid methyl ester (compound 25)

[0234] 0.2 g of methyl 2-4-dihydroxybenzoate and 0.23 g of diisopropylazodicarboxylate (DIAD) were dissolved in 2 mL of THF. To this mixturewas slowly added a mixture of 0.29 g of5-methyl-4-hydroxyethyl-3-phenyl-1,3-oxazole and 0.31 g of Ph₃P in 3 mLof THF and the mixture was subjected to Mitsunobu reaction. After thereaction mixture was allowed to stand over night, the solvent wasremoved. The resulting residue was purified by silicagel columnchromatography (ethyl acetate:benzene=1:5). After removing the solvent,the residue was recrystallized from benzene. 0.31 g (73.3%) of thecolorless objective compound was obtained. m.p.=133-134° C.

[0235] MASS(m/e):353(M+),217,185,136,104(BP),77,53

[0236] IR(cm⁻¹):1677,1617,1440,1320,1251,1188,1134

[0237]¹HNMR(CDCl₃) δ: 3.90 (S, 3H, —COOMe), 4.27 (t, 2H, —CH₂, J=6.34,6.84 Hz), 6.42 (dd, 1H, −aromatic, J=8.79 Hz), 6.46 (d, 1H, aromatic,J=2.44 Hz), 7.39-7.44 (m, 3H, aromatic), 7.72 (d, 1H, aromatic, J=9.28Hz), 7.97 (q, 2H, aromatic, J=7.33, 8.3 Hz), 10.93 (s, 1H, —OH)

Example 26-28

[0238] According to the procedure described in Example 11, compound 26(m.p.=211-213° C.), compound27 (m.p.=85-87° C.) and compound 28(m.p.=130-132° C.) were obtained.

Example 29-30

[0239] 2—Hydroxy-4-[2-(5-methyl-2-phenyl-1,3-oxazole4-yl)ethoxy]benzoicacid (compound 29)

[0240] 0.17 g of the compound obtained from Example 20 was dissolved in2 mL of MeOH:THF (1:1). To the solution was added 2 mL of 10% NaOH andthe mixture was refluxed for 1 hour. After removal of the solvent, theresidue was washed with ether, followed by acidification with 10% HCl.The resulting precipitate was filtered. Recrystallization from ethanolgave the colorless objective compound (0.13 g, 81.3%). m.p.=192-194° C.

[0241] MASS(m/e):339(M+),295,217,186,104(BP)

[0242] IR(cm⁻¹):2920,1655,1260,1170

[0243] According to the above mentioned procedure compound 30 wasobtained. (m.p.=246-266° C.).

Example 31-32

[0244] 2-Ethoxy-4-[2-(5-methyl-2-phenyl-1,3-oxazole4-yl)ethoxy]benzoicacid (compound 31)

[0245] (a)2-Ethoxy-4-[2-(5-methyl-2-phenyl-1,3-oxazole4-yl)ethoxy]benzoic acidmethyl ester

[0246] To a solution of the compound 25 (0.27 g) in DMF (5 mL) was addedK₂CO₃ (0.16 g) and EtI (0.07 mL) and the mixture was allowed to standover night. The reaction mixture was poured into water and the productwas extracted with ethyl acetate (30 mL). The ethyl acetate phase waswashed with water, satd. NaCl and dried over anhydrous Na₂SO₄ andfiltrated. Evaporation of the filtered gave a residue, from which 0.28 g(96.6%) of the colorless objective compound was obtained by silicagelcolumn chromatography (ethyl acetate:n-hexane =1:3).

[0247] MASS(m/e):381(M+),217,186,144,104(BP),77,51

[0248] IR(cm⁻¹):2926,1686,1605,1257,1194

[0249] (b)2-Ethoxy-4-[2-(5-methyl-2-phenyl-1,3-oxazole-4-yl)ethoxy]benzoic acid(compound 31)

[0250] The compound obtained from above mentioned Example 31-32 step (a)was hydrolyzed by the procedure in Example 29 and obtained the objectivecompound (0.22 g). m.p.=128-130° C.

[0251] MASS(m/e):367(M+),217,186,144,104(BP),77,51

[0252] IR(cm⁻¹):1686,1605,1572,1281,1263,1239,1191

[0253]¹HNMR(CDCl₃) δ: 2.99 (t, 2H, —CH₂—, J=6.84 Hz), 4.25 (q, 2H, oEt,J=6.84 Hz), 4.33 (t, 2H, —CH₂—, J=6.34, 6.84 Hz), 6.50 (d, 1H, aromatic,J=2.44 Hz), 6.55 (dd, 1H, aromatic, J=1.95 Hz), 7.41-7.44 (m, 3H,aromatic), 7.96-7.99 (m, 2H, aromatic), 8.10 (d, 1H, aromatic, J=8.79Hz)

[0254] And compound 25 was reacted with methoxy methylchloride to obtaincompound 32. m.p.=129-130° C.

Example 33-38

[0255] Each compounds of3-benzyl-4-nitrophenol-2,6-difluoro-4-nitrophenol and5-methyl-4-hydroxyethyl-2-phenyl-1,3-oxazole were subjected to Mitsunobureaction in a similar manner described in Example 25 and the nitrocompounds were obtained, followed by the procedures described in Example1 step (c) and step (d) yielded compound 33 (m.p.=155-156° C.),compound35 (m.p.=143-144° C.) and compound 36 (m.p.=78-80° C.). Further,Mitsunobu reaction of 2,4-dihydroxy-benzene sulfonamide and5-methyl-4-hydroxy-3-phenyl-1,3-oxazole yielded compound 34(m.p.=231-232° C.). Ethylation of the compound 34 yielded compound 37(m.p.=171-173° C.). Methyl 4-hydroxy-2-ethoxyphenoxy acetate was reactedin a similar manner and the resulting compound was hydrolyzed to obtaincompound 38 (m.p.=154-156° C.).

Example 39

[0256] 4-[2-(N-Methyl-N-2-pyridyl)aminoethoxy]-2-hydroxyphenyltrifluoromethane sulfonamide (compound 39)

[0257] (a) 4-[2-(N-Methyl-2—N-pyridyl)aminoethoxy]-2-hydroxynitrobenzene.

[0258] To a mixture of 2-(N-methyl, N-hydroxyethyl)-aminopyridine (0.35g) and 4-fluoro-2-methoxy-methyloxy-nitrobenzene in DMF (30 mL) wasadded NaH (0.12 g) and stirred at room temperature over night. Thereaction mixture was poured into ice-water and extracted with ethylacetate. The ethyl acetate extract was washed with satd. NHCl and driedover anhyd. Na₂SO₄ and filtered. After removal of solvent, the residuewas purified by silicagel column chromatography (ethylacetate:n-hexane=1:2). The oily objective compound (0.44 g, 57.1 %) wasobtained.

[0259] MASS(m/e):333(M+),121(BP),78,52

[0260] IR(cm⁻¹):2926,1596,1500,1425,1341,1287,1152

[0261] (b) 4-[2-(N-Methyl-N-2-pyridyl)aminoethoxy]-2-hydroxyphenyltrifluoromethanesulfonamide (compound 33)

[0262] The compound obtained from the above mentioned step (a) wasreduced with hydrogen in a similar manner described in Example 1 step(c) and the resulting compound was reacted with trifluoromethanesulfonicacid anhydride in a similar manner described in Experimental 1 step (d).After removing of the protection group (MOM, methoxymethyl), the residuewas recrystallized from the mixture of ethyl acetate and n-hexane toobtain the colorless objective compound (compound 33). mp-134-135° C.

[0263] MASS(m/e):391 (M+),135(BP),107,78

[0264] IR(cm−1):1611,1509,1419,1404,1227,1176,1146

[0265]¹HNMR(CDCl₃) δ: 3.14 (S, 3H, Me), 3.93 (t, 2H, —CH₂, J=5.37 Hz),4.11 (2H, —CH₂—, J=5.37 Hz), 6.37-6.43, 6.53-6.59 (m, m, 4H, aromatic,pyridine), 7.27 (d, 1H, aromatic, J=8.79 Hz), 7.46-7.51 (m, 1H,pyridine), 8.08 (d, 1H, pyridine, J=4.88 Hz)

Example 40-41

[0266] Compound 40 (m.p.=133-135° C.) and compound 41(m.p.=151-153° C.)were obtain from 4-fluoro-2-ethoxy-nitrobenzene by proceeding in asimilar manner described in Experimental 39 step (a).

Example 42-45

[0267] In stead of 2-(N-Methyl, N-hydroxyethyl) aminopyridine in Example39 step (a), 5-methyl-4-hydroxy-2-phenyl-1,3-oxazole was reacted in asimilar manner and the resulting compound was reacted withtrifluoromethanesulfonic acid anhydride to obtain compound 43(m.p.=169-171° C.). The compound obtained from Example 39 step (a) wasreacted with trifluoromethanesulfonic acid anhydride to obtain compound44 (m.p.=124-125° C.). Further, 2-(N-Methyl, N-hydroxyethyl)-aminopyridine in Example 39 step (a) was reacted with4-fluoro-2-methoxy-nitrobenzene and the resulting product was treatedwith in a similar manner described in Example 1 step (c) to obtain theoily objective compound 45.

Example 46-47

[0268] N-Butyl-2,4-dihydroxy-benzenesulfonamide and5-methyl-4-bromoethyl-2-phenyl-1,3-oxazole was reacted in a similarmanner described in Example 1 step (b) to obtain compound 46(m.p.=137-139° C.). After reacting 2,6-dibromo-4-hydroxy-benzoic acidmethyl ester and 5-methyl-4-bromoetyl-2-phenyl-1,3-oxazole, compound 47(m.p.=163-164° C.) was obtained.

Example 48-54

[0269] After chlorination of the compound of general formula (68), theresulting compound was reacted with 4-nitroaniline or correspondinganiline to obtain the compound of general formula (69), followed byreduction in a similar manner described in Example 1 and the resultingcompounds were treated in a similar manner described in Example 2. Thefollowing objective compounds were obtained. Compound 53 was hydrolyzedto obtain compound 54. Compound 48 (m.p.=147-149° C.), compound 49(m.p.=175-177° C.), compound 50 (m.p=166-168° C.), compound 51(m.p.=164-166° C.), compound 52 (m.p.=227-229° C.), compound 53 (oil),compound 54 (175° C., decomp.)

Example 55-56

[0270] After activation of carboxylic acid group in general formula (71)by the reported method (Bioorg.Med.Chem.Lett., 1995,1155), the resultingcompound was reacted with sulfamines in the presence of DBU to obtaincompound 55 (m.p.=150-152° C.) and compound 56 (m.p.=214-216° C.).

Example 57-59

[0271] In stead of 5-methyl-4-p-aminophenoxy-2-phenyl-1,3-oxazole inExample 2, 5-methyl-4-p-aminophenoxyethyl-2-p-tolyl-1,3-oxazole,5-methyl-4-p-aminophenoxyethyl-2-p-chlorophenyl-1,3-oxazole and5-methyl-4-p-aminophenoxyethyl-2-p-fluorophenyl-1,3-oxazole were reactedin a similar manner described in Example 2 to obtain the followingcompounds. Compound 57 (m.p.=173.5-175° C.), compound 58 (m.p.=189-190°C.), compound 59 (m.p.=161-163° C.).

Example 60-63

[0272] In stead of 5-methyl-4-p-aminophenoxy-2-phenyl-1,3-oxazole,5-isopropyl-4-p-aminophenoxy-ethyl-2-p-tolyl-1,3-oxazole,5-isopropyl-4-p-aminophenoxy-2-phenyl-1,3-oxazole,5-isopropyl-4-p-aminophenoxyethyl-2-p-fluorophenyl-1,3-oxazole and5-isopropyl-4-p-aminophenoxy-2-(3,5-di-t-butyl-4-hydroxy)phenyl-1,3-oxazolewere reacted in a similar manner described in Example 2 to obtain thefollowing compounds. Compound 60 (m.p.=190-191° C.), compound 61(m.p.=155-156° C.), compound 62 (m.p.=189-190° C.), compound 63(m.p.=142-144° C.). Example 64-66

[0273] 5-Isopropyl-4-hydroxyethyl-2-phenyl-1,3-oxazole,5-isopropyl-4-hydroxyethyl-2-p-phenyl-1,3-oxazole and5-isopropyl-4-hydroxyethyl-2-p-tolyl-1,3-oxazole were reacted with4-fluoro-2-ethoxy-nitrobenzene in a similar manner described in Example39 to obtain the following compounds. Compound 64 (m.p.=142-144° C.),compound 65 (m.p.=179-181° C.), Compound 66 (m.p.=122-124° C.)

Example 67-68

[0274] Each of5-methyl-4-hydroxyethyl-2-(p-ethoxycarbonylmethyloxy)phenyl-1,3-oxazoleand5-methyl-4-hydroxyethyl-2-(3,5-di-t-butyl-4-ethoxycarbonylmethyloxy)phenyl-1,3-oxazole were transformed to 5-methyl-4-p-nitrophenyl-2-(p-ethoxycarbonylmethyloxy)phenyl-1,3-oxazole and5-methyl-4-p-nitrophenyl-2-(3,5-di-t-butyl-4-ethoxycarbomethyloxy)phenyl-1,3-oxazoleusing a similar method described in Example 39. The resulting compoundswere hydrolyzed with 10% NaOH—MeOH to obtain the following compounds.Compound 67 (m.p.=167-168° C.), compound 68 (m.p.=196-198° C.)

Example 69

[0275] 5-Methyl-4-p-formylphenyl-2-phenyl-1,3-oxazole (1.0 g) wasdissolved in dichlolomethane (10 mL) and hydroxylamine-o-sulfonic acid(0.59 g) was added. The mixture was stirred for 30 minutes and theresulting precipitate was collected, followed by washing with water,MeOH and dichloromethane. 1.03 g of compound 69 was obtained.m.p.=165-167° C.

[0276] MASS(m/e):403(M+1),401(M−1)

Example70

[0277] According to a similar procedure, described in Example 2,5-methyl-4-aminophenoxyethyl-2-(3-t-butyl-4-hydroxy)phenyl-1,3-oxazolewere transformed to compound 70. m.p.=58-60° C.

[0278] Effects of the Invention

[0279] This invention concerns to novel ether and/or amide derivativeswhich enhance insulin action and show hypoglycemic activities with lowtoxicities and useful for antidiabetics.

What is claimed is:
 1. A compound of the general formula (I),R₁—A—R₂  (I)

(with the provisos that (i) when A is —O—, then n is 2 or 3 (ii) when Ais

then n is 1 or
 2. R₃ is OH—, CH₃SO₂NH—, CF₃SO₂NH—, CH₃SO₂NHCH₂—,CF₃SO₂NHCH₂—, HOOC—, CH₃OOC—,

HOOC—CH₂SO₂NH—, CF₃—CH₂SO₂NH—,

R₈—NHSO₂—, R₈—NHSO₂—CH₂—, HOOC—CH₂—O—, HSO₃N═CH—, or R₉—SO₂NHCO—; R₄ isH, OH, O-alkyl or O—CH₂OCH₃; R₅ is H, halogen atom, —CH₂COOH or OH; R₆and R₇ are hydrogen, t-butyl or pyrolidyl; R₈ is hydrogen or loweralkyl; R₉ is alkyl or thienyl; R₁₀ is lower alkyl) or a pharmaceuticallyacceptable salt.
 2. A compound of claim 1 wherein

(in which R₃ and R₄ have the above-mentioned meanings) or apharmaceutically acceptable salt.
 3. A compound of claim 1 wherein

or a pharmaceutically acceptable salt.
 4. A compound of claim 1 wherein

or a pharmaceutically acceptable salt.
 5. A compound of claim 1 wherein

(with the provisos that (i) when A is —O— then n is 2 or 3 (ii) when Ais

then n is 1 or
 2. R₅ is H or OH; R₆and R₇is H or t-butyl; R₁₀ is loweralkyl) or a pharmaceutically acceptable salt.
 6. A pharmaceuticalcomposition according to claim 1 for use as antidiabetics.
 7. A processfor the production of a compound of general formula (I) wherein A is—O—;

(R₄ has the above-mentioned meanings) through a compound of generalformula;

(in which R₂ and R₄ have the above-mentioned meaning) is reduced toobtain a compound of general formula;

(in which R₂ and R₄ have the above-mentioned meaning) is reacted withCH₃SO₂Cl or CF₃SO₂Cl to obtain the compound of the general formula (I).8. A process for the production of a compound of the general formula (I)wherein A is —O—;

through a compound of general formula;

(in which R₂ has the above-mentioned meaning) is reduced to obtain acompound of general formula;

(in which R₂ has the above-mentioned meaning) is reacted with CH₃SO₂Clor CF₃SO₂Cl to obtain the compound of general formula (I).
 9. A processfor the production of a compound of the general formula (I) wherein A is—O—; R has the above-mentioned meanings;

through a compound of general formula;

is reacted with a compound of general formula; X—R₂ (in which X is Br,tosyl or mesyl; R₂ has the above-mentioned meanings) to obtain acompound of general formula;

and followed by hydrolysis to obtain the compound of general formula(I).
 10. A process for the production of a compound of the generalformula (I) wherein A is —O—; R₂ has the above-mentioned meanings;

through a compound of general formula;

is reacted with a compound of general formula; HO—R₂ (in which R₂ hasthe above-mentioned meanings) to obtain a compound of general formula;

(in which R₂ has the above-mentioned meanings) and followed byhydrolysis to obtain the compound of general formula (I).
 11. A processfor the production of a compound of general formula (I) wherein A is—O—; R₂ has the above-mentioned meanings;

through a compound of general formula;

(in which R₂ has the above-mentioned meaning) is reacted with

to obtain a compound of general formula;

(in which R₂ has the above-mentioned meaning) after debenzylation, isconverted to a compound of general formula;

(in which R₂ has the above-mentioned meanings) is reacted with CH₃SO₂Clor CF₃SO₂Cl to obtain the compound of general formula (I).
 12. A processfor the production of a compound of the general formula (I) wherein A is—O—; R₂ has the above-mentioned meanings;

through a compound of general formula;

is reduced to obtain a compound of general formula;

(in which R₂ has the above-mentioned meanings) then reacted withEtOOC—CH₂—SO₂Cl to obtain a compound of general formula;

(in which R₂ has the above-mentioned meanings) and followed byhydrolysis to obtain the compound of general formula (I).
 13. A processfor the production of a compound of the general formula (I) wherein A is—O—; R₂ has the above-mentioned meanings;

through a compound of general formula;

(in which R₂ has the above-mentioned meanings) is reduced to obtain acompound of general formula;

(in which R₂ has the above-mentioned meanings) and then reacted with

to obtain

(in which R₂ has the above-mentioned meaning) and then hydrolyzed toobtain the compound of general formula (I).
 14. A process for theproduction of a compound of the general formula (I) wherein A is —O—; R₂has the above-mentioned meanings;

through a compound of general formula;

(in which R₂ has the above-mentioned meanings) is reduced to obtain acompound of general formula;

(in which R₂ has the above-mentioned meanings) and then reacted with

to obtain the compound of genaral formula (I).
 15. A method ofmanufacturing a compound of the general formula (I) wherein A is —O—; R₂has the above-mentioned meanings;

which comprises reduction of a compound of general formula;

(in which R₂ has the above-mentioned meanings) to obtain a compound ofgeneral formula;

(in which R₂ has the above-mentioned meanings) and then reacted withmethyloxalate to obtain a compound of general formula;

(in which R₂ has the above-mentioned meaning) and subjected tohydrolyzed to obtain the compound of genaral formula (I).
 16. A methodfor manufacturing a compound of the genaral formula (I) wherein A is—O—; R₂ has the above-mentioned meanings;

which comprises a reaction of

with a compound of general formula; HO—R₂ (in which R₂ has theabove-mentioned meanings) in the presence of NaH to obtain a compound ofgeneral formula (I).
 17. A method for manufacturing a compound of thegeneral formula (I) wherein A is —O—; R₂ has the above-mentionedmeanings;

which comprises a reaction of a compound of general formula;

(in which R₂ has the above-mentioned meanings) with thienyl sulfonamideor methyl sulfonamide in the presence of 1,8-Diazabicyclo[5,4,0]undeca-7-en to obtain the compound of general formula (I).
 18. Amethod for manufacturing a compound of the general formula (I) wherein Ais —O—; R₂ has the above-mentioned meanings;

which comprises a reaction of

with a compound of general formula; HOOC—R₂ (in which P2 has theabove-mentioned meanings) to obtain the compound of general formula (I).19. A method for manufacturing a compound of the general formula (I)wherein A is —O—; R₂ has the above-mentioned meanings;

which comprises a reaction of a compound of general formula;

(in which R₂ has the above-mentioned meanings) with H₂NOSO₃H to obtainthe compound of general formula (I).